Doxorubicin-induced Immunogenic Cell Death Impairs Tumor Progression and Distant Metastasis in a 4T1 Breast Cancer Tumor Model.

INTRODUCTION: Cancer is an individual disease and its formation and development are specific to each host. Conventional treatments are ineffective in complex cases, such as metastasis, and have severe adverse side effects. New strategies are needed to address the problem, and the use of immunogenic cell death (ICD) as a trigger or booster of the immune system through the exposure of damage-associated molecular patterns, along with tumor antigens, by cancerous cells is presented as an immunization approach in this work. METHODS: For this purpose, 4T1 cells were exposed to doxorubicin (DOX) for 24 hours and then, these cells undergoing ICD were subcutaneously administered to mice. The ICD induction by DOX on 4T1 was assessed by flow cytometry and image analysis. This immunization process was performed three times and after the last administration, the immunized mice were challenged with a subcutaneous xenograft of live cancer cells. RESULTS: The results demonstrate that the mice immunized with cells undergoing ICD after exposure to DOX presented no primary tumor or indications of distant metastatic lesion development. CONCLUSION: In summary, our findings indicate that the immunization process utilizing ICD is indeed efficacious in managing this aggressive form of pre-clinical breast cancer.

A Snake Venom Peptide and Its Derivatives Prevent Aß42 Aggregation and Eliminate Toxic Aß42 Aggregates In Vitro.

Over a century has passed since Alois Alzheimer first described Alzheimer's disease (AD), and since then, researchers have made significant strides in understanding its pathology. One key feature of AD is the presence of amyloid-ß (Aß) peptides, which form amyloid plaques, and therefore, it is a primary target for treatment studies. Naturally occurring peptides have garnered attention for their potential pharmacological benefits, particularly in the central nervous system. In this study, nine peptide derivatives of Crotamine, a polypeptide from Crotalus durissus terrificus Rattlesnake venom, as well as one d-enantiomer, were evaluated for their ability to modulate Aß42 aggregation through various assays such as ThT, QIAD, SPR, and sFIDA. All tested peptides were able to decrease Aß42 aggregation and eliminate Aß42 aggregates. Additionally, all of the peptides showed an affinity for Aß42. This study is the first to describe the potential of crotamine derivative peptides against Aß42 aggregation and to identify a promising d-peptide that could be used as an effective pharmacological tool against AD in the future.

Octovespin, a peptide bioinspired by wasp venom, prevents cognitive deficits induced by amyloid-ß in Alzheimer's disease mouse model.

Approximately 46.8 million people have been diagnosed worldwide with dementia, of which the most common type is Alzheimer's disease (AD). Since the current AD treatment is incipient and limited, it is essential to develop new drugs to prevent AD. Considering that evolutionary pressure selected animal venom compounds that are very specific for a unique target, those can be a potential drug against AD. Octovespin was modified from occidentalin-1202, which is a peptide isolated from Polybia occidentalis wasp venom. In this context, this study evaluated the effect of treatment with octovespin against Amyloid-ß (Aß)-induced toxicity, which is postulated to be one of the main causes of AD, in both in vitro and in vivo tests. In vitro, octovespin was able to prevent Aß aggregation in a ThT assay. In vivo, octovespin (0.15 nmol/animal) reverses memory impairment that is due to Aß toxicity, in the Morris Water Maze and Novel Object Recognition Test. Our results suggested that octovespin is a potential drug for the treatment of AD, due to its ability to avoid Aß aggregation in vitro and to prevent Aß -induced memory deficit in mice.

Sex-Related Motor Deficits in the Tau-P301L Mouse Model.

The contribution of mouse models for basic and translational research at different levels is important to understand neurodegenerative diseases, including tauopathies, by studying the alterations in the corresponding mouse models in detail. Moreover, several studies demonstrated that pathological as well as behavioral changes are influenced by the sex. For this purpose, we performed an in-depth characterization of the behavioral alterations in the transgenic Tau-P301L mouse model. Sex-matched wild type and homozygous Tau-P301L mice were tested in a battery of behavioral tests at different ages. Tau-P301L male mice showed olfactory and motor deficits as well as increased Tau pathology, which was not observed in Tau-P301L female mice. Both Tau-P301L male and female mice had phenotypic alterations in the SHIRPA test battery and cognitive deficits in the novel object recognition test. This study demonstrated that Tau-P301L mice have phenotypic alterations, which are in line with the histological changes and with a sex-dependent performance in those tests. Summarized, the Tau-P301L mouse model shows phenotypic alterations due to the presence of neurofibrillary tangles in the brain.

In Vitro and In Vivo Efficacies of the Linear and the Cyclic Version of an All-d-Enantiomeric Peptide Developed for the Treatment of Alzheimer's Disease.

Multiple sources of evidence suggest that soluble amyloid ß (Aß)-oligomers are responsible for the development and progression of Alzheimer's disease (AD). In order to specifically eliminate these toxic Aß-oligomers, our group has developed a variety of all-d-peptides over the past years. One of them, RD2, has been intensively studied and showed such convincing in vitro and in vivo properties that it is currently in clinical trials. In order to further optimize the compounds and to elucidate the characteristics of therapeutic d-peptides, several rational drug design approaches have been performed. Two of these d-peptides are the linear tandem (head-to-tail) d-peptide RD2D3 and its cyclized form cRD2D3. Tandemization and cyclization should result in an increased in vitro potency and increase pharmacokinetic properties, especially crossing the blood-brain-barrier. In comparison, cRD2D3 showed a superior pharmacokinetic profile to RD2D3. This fact suggests that higher efficacy can be achieved in vivo at equally administered concentrations. To prove this hypothesis, we first established the in vitro profile of both d-peptides here. Subsequently, we performed an intraperitoneal treatment study. This study failed to provide evidence that cRD2D3 is superior to RD2D3 in vivo as in some tests cRD2D3 failed to show equal or higher efficacy.

PEAß Triggers Cognitive Decline and Amyloid Burden in a Novel Mouse Model of Alzheimer's Disease.

Understanding the physiopathology of Alzheimer's disease (AD) has improved substantially based on studies of mouse models mimicking at least one aspect of the disease. Many transgenic lines have been established, leading to amyloidosis but lacking neurodegeneration. The aim of the current study was to generate a novel mouse model that develops neuritic plaques containing the aggressive pyroglutamate modified amyloid-ß (pEAß) species in the brain. The TAPS line was developed by intercrossing of the pEAß-producing TBA2.1 mice with the plaque-developing line APPswe/PS1ΔE9. The phenotype of the new mouse line was characterized using immunostaining, and different cognitive and general behavioral tests. In comparison to the parental lines, TAPS animals developed an earlier onset of pathology and increased plaque load, including striatal pEAß-positive neuritic plaques, and enhanced neuroinflammation. In addition to abnormalities in general behavior, locomotion, and exploratory behavior, TAPS mice displayed cognitive deficits in a variety of tests that were most pronounced in the fear conditioning paradigm and in spatial learning in comparison to the parental lines. In conclusion, the combination of a pEAß- and a plaque-developing mouse model led to an accelerated amyloid pathology and cognitive decline in TAPS mice, qualifying this line as a novel amyloidosis model for future studies.

Characterization of two peptides isolated from the venom of social wasp Chartergellus communis (Hymenoptera: Vespidae): Influence of multiple alanine residues and C-terminal amidation on biological effects.

Chatergellus communis is a wasp species endemic to the neotropical region and its venom constituents have never been described. In this study, two peptides from C. communis venom, denominated Communis and Communis-AAAA, were chemically and biologically characterized. In respect to the chemical characterization, the following amino acid sequences and molecular masses were identified: Communis: Ile-Asn-Trp-Lys-Ala-Ile-Leu-Gly-Lys-Ile-Gly-Lys-COOH (1340.9Da) Communis-AAAA: Ile-Asn-Trp-Lys-Ala-Ile-Leu-Gly-Lys-Ile-Gly-Lys-Ala-Ala-Ala-Ala-Val-Xle-NH2 (1836.3Da). Furthermore, their biological effects were compared, accounting for the differences in structural characteristics between the two peptides. To this end, three biological assays were performed in order to evaluate the hyperalgesic, edematogenic and hemolytic effects of these molecules. Communis-AAAA, unlike Communis, showed a potent hemolytic activity with EC50=142.6µM. Moreover, the highest dose of Communis-AAAA (2nmol/animal) induced hyperalgesia in mice. On the other hand, Communis (10nmol/animal) was able to induce edema but did not present hemolytic or hyperalgesic activity. Although both peptides have similarities in linear structures, we demonstrated the distinct biological effects of Communis and Communis-AAAA. This is the first study with Chartegellus communis venom, and both Communis and Communis-AAAA are unpublished peptides.